enclomiphene and Hypogonadism

Enclomiphene (Androxal), in development by Repros Therapeutics Inc, is a non-steroidal estrogen receptor antagonist that promotes gonadotropin-dependent testosterone secretion by the testes. Enclomiphene constitutes the trans-stereoisomer of clomiphene citrate, a drug that has been widely prescribed for several decades for the treatment of female ovulatory dysfunction. Because of the antagonistic effects of enclomiphene, the drug has the potential to increase serum testosterone levels in men with secondary hypogonadism by restoring physiological endogenous testosterone secretion while maintaining testicular volume and, potentially, spermatogenesis. In clinical trials conducted to date, enclomiphene demonstrated significant efficacy in the physiological restoration of testosterone levels in males with secondary hypogonadism. The compound also exhibited an unanticipated favorable effect on fasting plasma glucose; this result has been accompanied by rapidly accumulating evidence from other researchers for a bidirectional relationship between low serum testosterone and obesity/metabolic syndrome (syndrome X) in men. Short-term clinical safety data for enclomiphene have been satisfactory and equivalent to safety data for testosterone gels and placebo. Enclomiphene demonstrates promise in the management of secondary hypogonadism associated with obesity, metabolic syndrome and, possibly, infertility, and should undergo placebo-controlled, randomized clinical trials for these indications.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Clomiphene; Enclomiphene; Estrogen Antagonists; Humans; Hypogonadism; Male; Spermatogenesis; Testosterone

To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism.. Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel(®) 1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18-60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2-10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study.. TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group.. Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained.

Topics: Administration, Oral; Adolescent; Adult; Circadian Rhythm; Double-Blind Method; Enclomiphene; Estrogen Antagonists; Follicle Stimulating Hormone; Hormone Replacement Therapy; Humans; Hypogonadism; Luteinizing Hormone; Male; Middle Aged; Obesity; Patient Safety; Sperm Count; Spermatogenesis; Testosterone; Treatment Outcome; Young Adult

To determine the effect of enclomiphene citrate in men with secondary hypogonadism.. Phase II clinical trial.. Community dwelling men making visits to physician offices.. Men with secondary hypogonadism.. Oral administration of enclomiphene citrate or 1% topical T gel.. Luteinizing hormone, FSH, T, and semen analysis.. Treatment with enclomiphene citrate resulted in increased morning serum T, E2, and LH levels similar to those obtained with a topical T gel in men with secondary hypogonadism. Follicle-stimulating hormone and LH were increased with enclomiphene, and sperm counts were conserved.. Enclomiphene citrate reverses the two hallmarks of secondary hypogonadism, namely, low serum total T and low or inappropriately normal LH while preserving sperm production.. NCT01270841 (ClinicalTrials.gov Identifier NCT01270841).

Topics: Administration, Oral; Administration, Topical; Adult; Enclomiphene; Estradiol; Humans; Hypogonadism; Luteinizing Hormone; Male; Middle Aged; Oligospermia; Sex Hormone-Binding Globulin; Testosterone; Up-Regulation

Clomiphene citrate is employed off-label in men who have low testosterone and for the restoration of sperm counts in men who have used exogenous testosterone. Clomiphene is a mixture of two diastereoisomers: zuclomiphene and enclomiphene. We evaluated enclomiphene citrate in men with secondary hypogonadism.. Our aim was to compare oral enclomiphene citrate as an alternative to topical testosterone.. Blood levels of total testosterone (TT), estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, thyroid stimulation hormone, prolactin, and insulin-like growth factor 1 IGF-1 were measured at certain times after treatment with each agent. Sperm parameters were determined at the same visits. Free testosterone (FT) was calculated.. This was a proof-of-principle, randomized, open-label, fixed dose, active-control, two-center phase IIB study in 12 men with secondary hypogonadism treated previously with topical testosterone.. After discontinuation of topical testosterone, morning TT values averaged 165 ± 66 pg/dL. After 3 months, there was a significant rise in men receiving enclomiphene citrate and gel that was sustained for 3 months. At 6 months, TT levels were 545 ± 268 and 525 ± 256 pg/dL for groups receiving the gel and enclomiphene citrate, respectively. Only men in the enclomiphene citrate group demonstrated increased LH and FSH. TT decreased one month posttreatment to pretreatment values. Enclomiphene citrate elevated sperm counts in seven out of seven men at 3 months and six out of six men at 6 months with sperm concentrations in the 75-334 × 10(6) /mL range. The gel was ineffective in raising sperm counts above 20 × 10(6) /mL for all five men at 3 months and raised counts in only two or five men at 6 months. At follow-up, only enclomiphene citrate treatment was associated with elevated sperm counts.. Enclomiphene citrate increased testosterone and sperm counts. Concomitant changes in LH and FSH suggest normalization of endogenous testosterone production and restoration of sperm counts through the hypothalamic-pituitary-testicular axis.

Topics: Administration, Cutaneous; Administration, Oral; Adult; Biomarkers; Enclomiphene; Estradiol; Follicle Stimulating Hormone, Human; Gels; Hormone Replacement Therapy; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Insulin-Like Growth Factor I; Luteinizing Hormone; Male; Middle Aged; Prolactin; Sex Hormone-Binding Globulin; Sperm Count; Spermatogenesis; Testis; Testosterone; Thyrotropin; Treatment Outcome

YES. For both normal-weight and obese men with low testosterone levels and hypogonadal symptoms, selective estrogen receptor modulators (SERMs), such as clomiphene citrate (CC) and enclomiphene citrate (EC), appear to be effective and safe for improving serum testosterone levels (strength of recommendation [SOR]: C, disease-oriented outcomes from randomized controlled trials [RCTs] and cohort studies). Studies also show that symptom improvement is comparable to that with exogenous testosterone replacement and similar to eugonadal men (SOR: B, patient-oriented outcomes from retrospective cohort studies).

Topics: Clomiphene; Enclomiphene; Humans; Hypogonadism; Male; Selective Estrogen Receptor Modulators; Testosterone

To determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in men with hypogonadism on long-term clomiphene citrate (CC) therapy, and to determine whether patient age, body mass index (BMI) or duration of therapy were predictive of relative concentrations of ENC and ZUC.. Men already receiving CC 25 mg daily therapy for secondary hypogonadism for a minimum of 6 weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone, free testosterone, oestradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) before initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, BMI and medical comorbidites were recorded. Serum samples were obtained at the time of enrolment to determine ENC and ZUC concentrations.. Long-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for the development of a pure selective oestrogen receptor antagonist for the treatment of men with hypogonadism.

Topics: Adult; Aged; Clomiphene; Enclomiphene; Estrogen Antagonists; Humans; Hypogonadism; Male; Middle Aged; Time Factors; Young Adult; Zuclomiphene

Topics: Enclomiphene; Estrogen Antagonists; Humans; Hypogonadism; Male; Obesity; Testosterone

Topics: Enclomiphene; Humans; Hypogonadism; Male; Oligospermia; Testosterone

Topics: Enclomiphene; Humans; Hypogonadism; Male; Oligospermia; Testosterone

Hypogonadism has a number of important clinical consequences related to androgen deficiency and impaired spermatogenesis. The cause of this condition is multifactorial and can result from hypothalamic, pituitary or gonadal dysfunction as well as factors that affect hormonal signaling along the hypothalamic-pituitary-gonadal axis. While testosterone replacement is the most common treatment, it can paradoxically lead to infertility, and may be a less physiologic therapy for patients with secondary hypogonadism due to pituitary dysfunction. Clomiphene citrate, and its derivatives, may allow for restoration of gonadal function by restoring physiologic pituitary function in a subset of patients with hypogonadism.

Topics: Androgens; Clomiphene; Enclomiphene; Estrogen Antagonists; Humans; Hypogonadism; Infertility, Male; Male; Pituitary Gland